TY - JOUR T1 - Langerhans islets induce anti-tumor immunity at the expense of glycemic control and predict chemotherapy response in pancreatic cancer JF - bioRxiv DO - 10.1101/2021.03.13.435100 SP - 2021.03.13.435100 AU - Azaz Ahmed AU - Pornpimol Charoentong AU - Rosa Klotz AU - Sophia Köhler AU - Meggy Suarez-Carmona AU - Nektarios A. Valous AU - Dyke Ferber AU - Mathias Heikenwälder AU - Nathalia Giese AU - Thilo Hackert AU - Fee Klupp AU - Martin Schneider AU - Thomas Schmidt AU - Christoph Springfeld AU - Yakup Tanriver AU - Christine S. Falk AU - Laurence Zitvogel AU - Inka Zörnig AU - Dirk Jäger AU - Niels Halama Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/03/15/2021.03.13.435100.abstract N2 - Induction of anti-tumor immunity in pancreatic ductal adenocarcinoma (PDA) is an unresolved challenge. Systematic investigation of the microenvironment of primary pancreatic tumors revealed a role of endocrine Langerhans islets in the coordination of immune activation. We found that intratumoral β-cells, regulated via STAT3, secrete C-C motif chemokine ligand 27 (CCL27) and thereby promote a TH1 phenotype in the microenvironment resulting in an enhanced T cell infiltration and prolonged patient survival. The local effect can be abrogated in a patient-based human explant model by inhibition of the CCL27 receptor CCR10. This defense mechanism is paralleled by an impaired metabolic function of Langerhans islets with reduced insulin levels resulting in a dysregulation of glycemic control in patients. Based on these findings, screening of PDA cases (n= 2264) led to the identification of type 2 diabetes mellitus (T2DM) and extractable glycated haemoglobin (HbA1c) levels as response markers for neoadjuvant chemotherapy with fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX). Collectively these data provide insights into the interconnection of T2DM and PDA, and link declining glycemic control to therapeutic efficacy, which can be utilized as a tool for clinical decision-making and improve patient management.Competing Interest StatementThe authors have declared no competing interest. ER -